Maladaptive myelination promotes generalized epilepsy progression

Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.


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Policy information about availability of computer code Data collection Representative images and images used to quantify TUNEL positive OPCs, TUNEL positive oligodendrocytes, microglia and astrocytes were collected with a Zeiss confocal microscope, LSM800 or LSM700 model, using Zen 2.1 or 2.3 software, as indicated in the Methods. Fluorescent images used to quantify cells with unbiased stereology were collected with Stereo Investigator software (MBF Bioscience, versions 2017-2020). Continuous real-time EEG was recorded with Open Ephys software (https://open-ephys.org, version 0.4.4.1).

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Cell counts were performed by unbiased stereology using Stereo Investigator software (MBF Bioscience, versions 2017-2020). ImageJ software (https://imagej.nih.gov/ij/, versions 1.53a -2.0) and Fiji software (imagej.net/software/fiji/, version 2.1.0) were used to quantify g-ratios from transmission electron micrographs and cell counts where indicated in the Methods. Unmyelinated axons and myelinated axons were counted from transmission electron micrographs. Seizures from EEG recordings and EEG coherence were quantified using custom Matlab software, version R2019B, available at: https://github.com/huguenardlab/EEG. GraphPad Prism software (GraphPad Software, versions 8 and 9) was used to perform statistical analyses.
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